Inhibidores de los canales de Calcio en Ictus Isquemico
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Transcript of Inhibidores de los canales de Calcio en Ictus Isquemico
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Calcium antagonists for acute ischemic stroke (Review)
Zhang J, Yang J, Zhang C, Jiang X, Zhou H, Liu M
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published inThe Cochrane Library2012, Issue 5
http://www.thecochranelibrary.com
Calcium antagonists for acute ischemic stroke (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
http://www.thecochranelibrary.com/http://www.thecochranelibrary.com/ -
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T A B L E O F C O N T E N T S
1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
11DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
16CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
53DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Calcium antagonists versus control in acute ischemic stroke, Outcome 1 Primary outcome atend of follow-up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Analysis 1.2. Comparison 1 Calcium antagonists versus control in acute ischemic stroke, Outcome 2 Death at end of
treatment period. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Analysis 1.3. Comparison 1 Calcium antagonists versus control in acute ischemic stroke, Outcome 3 Death at end of
follow-up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Analysis 1.4. Comparison 1 Calcium antagonists versus control in acute ischemic stroke, Outcome 4 Recurrence of stroke
at end of follow-up. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Analysis 1.5. Comparison 1 Calcium antagonists versus control in acute ischemic stroke, Outcome 5 Adverse events (all)
during treatment period. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Analysis 1.6. Comparison 1 Calcium antagonists versus control in acute ischemic stroke, Outcome 6 Hypotension during
treatment period (reason to stop treatment). . . . . . . . . . . . . . . . . . . . . . . . 63
Analysis 1.7. Comparison 1 Calcium antagonists versus control in acute ischemic stroke, Outcome 7 Mean systolic blood
pressure during or at end of treatment. . . . . . . . . . . . . . . . . . . . . . . . . . 64Analysis 2.1. Comparison 2 Calcium antagonists versus control: subgroup analysis, Outcome 1 Primary outcome by route
of administration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Analysis 2.2. Comparison 2 Calcium antagonists versus control: subgroup analysis, Outcome 2 Primary outcome by dose:
indirect comparisons. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Analysis 2.3. Comparison 2 Calcium antagonists versus control: subgroup analysis, Outcome 3 Primary outcome by dose:
direct comparisons. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Analysis 2.4. Comparison 2 Calcium antagonists versus control: subgroup analysis, Outcome 4 Primary outcome by time
of start of treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Analysis 3.1. Comparison 3 Calcium antagonists versus control: sensitivity analysis, Outcome 1 Primary outcome in
multicenter placebo controlled trials. . . . . . . . . . . . . . . . . . . . . . . . . . . 72
Analysis 3.2. Comparison 3 Calcium antagonists versus control: sensitivity analysis, Outcome 2 Publication status. . 73
74APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
77WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .77HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
77CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
77DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
78SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
78INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
iCalcium antagonists for acute ischemic stroke (Review)
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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[Intervention Review]
Calcium antagonists for acute ischemic stroke
Jing Zhang1, Jie Yang2, Canfei Zhang1, Xiaoqun Jiang1, Hongqing Zhou1, Ming Liu1
1Department of Neurology, West China Hospital, Sichuan University, Chengdu, China. 2Department of Neurology, Nanjing First
Hospital, Nanjing Medical University, Nanjing, China
Contact address: Ming Liu, Department of Neurology, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu,
Sichuan, 610041, [email protected].
Editorial group:Cochrane Stroke Group.
Publication status and date:New search for studies and content updated (no change to conclusions), published in Issue 5, 2012.
Review content assessed as up-to-date: 25 January 2012.
Citation: Zhang J, Yang J, Zhang C, Jiang X, Zhou H, Liu M. Calcium antagonists for acute ischemic stroke.Cochrane Database of
Systematic Reviews2012, Issue 5. Art. No.: CD001928. DOI: 10.1002/14651858.CD001928.pub2.
Copyright 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
Background
The sudden loss of blood supply in ischemic stroke is associated with the increase of calcium ions within neurons. Inhibiting this
increase could protect neurons and hence might reduce neurological impairment, disability and handicap after stroke.
Objectives
To determine whether calcium antagonists reduce the risk of death or dependency after acute ischemic stroke. To investigate theinfluence of different drugs, dosages, routes of administration, time intervals after stroke and trial design on the risk of a primary
outcome.
Search methods
We searched the Cochrane Stroke Group Trials Register (January 2012), MEDLINE (1950 to December 2011), EMBASE (1980 to
December 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2011 issue 4) and fourChinese databases (December 2011): Chinese Biological Medicine Database (CBM-disc), China National Knowledge Infrastructure
(CNKI), Chinese scientific periodical database of VIP information and Wanfang Data. We also contacted trialists and researchers.
Selection criteria
All truly randomized trials comparing a calcium antagonist with control in patients with acute ischemic stroke.
Data collection and analysis
Two authors assessed all trials and extracted the data. We used death or dependency at the end of long-term follow-up (at least three
months) in activities of daily living as the primary outcome. Analyses were, if possible, intention-to-treat.
Main results
We included 34 trials including 7731 patients.There was no effect of calcium antagonists on the primary outcome (risk ratio (RR)1.05; 95% confidence interval (CI) 0.98 to 1.13), or on death at the end of follow-up (RR 1.07, 95% CI 0.98 to 1.17). Comparisons
of different doses of nimodipine suggested that the highest doses were associated with poorer outcome.
1Calcium antagonists for acute ischemic stroke (Review)
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Authors conclusions
No evidence is available using calcium antagonists in patients with acute ischemic stroke is effective.
P L A I N L A N G U A G E S U M M A R Y
Calcium antagonists for acute ischemic stroke
The majority of ischemic strokes are due to blockage of an artery in the brain by a blood clot. The area of brain supplied by that artery
rapidly becomes damaged. Some of the damage to brain cells occurs because of a build-up of calcium ions inside the cells. Calcium
antagonists might reduce the damage by preventing calcium ions entering the cells. We searched for trials which assessed the effects
of calcium antagonists (given either by mouth or by intravenous injection) in patients with ischemic stroke. We found 34 studies,
including 7731 patients, that were suitable for inclusion in the review. There was no difference in deaths or survival free of disability
between patients who received calcium antagonists and those who did not. Patients who received calcium antagonists by intravenous
injection were slightly worse overall than those who received the drugs by mouth. In conclusion, the authors of this Cochrane review
found no evidence that giving calcium antagonists after acute ischemic stroke could save lives or reduce disability.
B A C K G R O U N D
Calcium antagonists may act as neuroprotective drugs by dimin-
ishing the influx of calcium ions through the voltage sensitive cal-
cium channels. One Cochrane review published in The CochraneLibraryhas already demonstrated that calcium antagonists couldreduce the risk of a primary outcome and secondary ischemia af-
ter aneurysmal subarachnoid hemorrhage (SAH) (Mees 2008).Of
course, there is a difference between the treatment of ischemic
stroke and the treatment of SAHs. At the same time, in stroke,
medication will be started after the onset of ischemia instead of
being given before. In view of the evidence on the existence of
an ischemic penumbra (Siesjo 1978), where brain tissue may
survive in ischemic periods of variable and as yet not precisely
determined duration, a therapeutic effect may be present when
administration starts up to several hours after stroke onset. There-
fore, it is necessary to test whether this kind of drug can play a
neuroprotective role and improve neurological impairment.
Description of the condition
Stroke is the second more common cause of death and the leading
cause of disability worldwide (Liu 2007). Approximately 87% of
all strokes are ischemic (i.e. due to a blockage of an artery in the
brain) (AHA 2007), which leads to the affected area being starved
of oxygen. Massive calcium influx entering into the cells is a final
common pathway that leads to cell death (Siesjo 1989). Therefore,
it is necessary to test any promising strategy that could help brain
cells recover by blocking calcium ions.
Description of the intervention
Calcium antagonists reduce the influx of calcium into the cell
through blocking calcium channels. Thus, a rationale for the use
of calcium antagonists for preventing secondary ischemia is based
on the notion that these drugs can counteract the influx of calcium
into the vascular smooth-muscle cell, thereby decreasing the rate
of vasospasm. Animal experiments have indicated that calcium
antagonists administeredafter cerebral ischemia may be effective inreducing infarct volume andlead to improvements in neurological
outcome (Germano 1987;Steen 1983). After their introduction
into clinical practice it was discoveredthat calcium antagonists also
had neuroprotective properties (Mees 2008). Calcium antagonists
reduce the risk of primary outcome and secondary ischemia after
SAH (Mees 2008), and nimodipine, a typical calcium antagonist,
has been shown to be effective in decreasing the occurrence of
death and disability (primary outcome) after SAH and traumatic
SAH in humans (Di Mascio 1994;Harders 1996;Pickard 1989).
We wondered whether calcium antagonists could have the same
effects in ischemic stroke patients.
How the intervention might work
Some meta-analyses with a more limited scope (restricted to ni-
modipine and completed before some recent trials were available)
have been performed (Di Mascio 1994; Gelmers 1990; Mohr
1994). In these meta-analyses, a beneficial effect of nimodipine
was not demonstrated, except in one subgroup analysis. This sub-
group analysis (patients treated within 12 hours of stroke onset)
2Calcium antagonists for acute ischemic stroke (Review)
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suggested that early treatment was effective and might lead to a
38% reduction in the odds of the primary outcome occurring
(Mohr 1994). Any subgroup analysis showing a beneficial effect
should be interpreted with caution, since there is always the dan-
ger that it might be a chance finding (Counsell 1994).
Why it is important to do this review
Calcium antagonists could protect neurons and hence might
reduce neurological impairment, disability and handicap after
stroke. Many calcium antagonists have been tested in randomized
controlled trials (RCTs) in patients with acute ischemic stroke,
but none of these trials have demonstrated a convincing benefi-
cial effect. However, the sample size might be too small to show
a result or significant clinical effect. For this reason a systematic
review was necessary. The last version of this Cochrane review was
published in 2000. Since then more trials have been published.
Therefore, we conducted this updated review to provide more up-to-date evidence for clinical practice.
O B J E C T I V E S
To determine whether using of calcium antagonists in patients
with acute ischemic stroke could (1) reduce the number of patients
who, at the end of follow-up, are either dead or severely disabled,
(2) reduce the risk of death during the treatment period or at the
end of follow-up and to make comparisons for different calcium
antagonist regimens (different drugs, oral or intravenous admin-istration, different dosages and various time intervals from onset
of symptoms until start of treatment) and different trial designs
(multicenter placebo-controlled trial, publication status).
M E T H O D S
Criteria for considering studies for this review
Types of studies
We included all RCTs of calcium antagonists versus control
(placebo or standard medical treatment alone). We also included
trials comparing different routes of administration (oral versus in-
travenous administration) and different doses. We excluded trials
that were not truly randomized.
Types of participants
Patients with presumed or definite acute ischemic stroke that were
randomized within 14 days after stroke onset. All were confirmed
through computerized tomography (CT) or magnetic resonance
(MR)scanning.Two studies (Chandra 1995; Lowe 1989) included
some hemorrhagic stroke patients (255 patients included in total)but, since we could not extract the information for the ischemic
stroke patients only, we included all randomized patients.
Types of interventions
We included all types of calcium antagonists, given in any dose, by
the intravenous or oral route. These were defined as agents whose
principal mode of action is to inhibit the influx of calcium into
cells by way of the voltage-sensitive calcium channels.
We excluded trials that were confounded by the treatment or con-
trol group receiving another active therapy that had not been fac-
tored into the randomization.
Types of outcome measures
Primary outcomes
Primary outcome: defined as death (all-cause case fatality) or de-
pendency in activities of daily living at long-term follow-up (at
least three months). For assessing dependency, we used the follow-
ing available functional health scales: the Modified Rankin or Ox-
ford Handicap Scale (dependency > 3) (Bamford 1989), Glasgow
Outcome Scale (dependency < 4) (Jennet 1975), the Barthel Index
(dependency < 60) (Mahoney 1965), Toronto Stroke Scale (de-
pendency > 3) (Norris 1982) or the disability item in the Mathew
Impairment Scale (dependency = 7) (Mathew 1972). If more than
one scale was available, we selected the one with the smallest num-
ber of missing values (see theCharacteristics of included studies
table for details).
Secondary outcomes
1. Death from any cause during the scheduled treatment
period.
2. Death from any cause during long-term follow-up (at least
3 months).
3. Recurrent stroke during long-term follow-up.
4. Adverse effects of the drug (e.g. impairment of kidney
function, impairment of liver function, skin irritation, local
infusion-related irritation, nausea, etc) during the scheduled
treatment period.
5. Hypotension: substantial fall in blood pressure during the
scheduled treatment period.
6. Mean systolic blood pressure during the treatment period.
We recorded these events if they were mentioned as such in the
original paper, thus the definitions of the investigators were used.
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Search methods for identification of studies
See the Specialized register section in the Cochrane Stroke
Group module. We searched for trials in all languages and ar-
ranged translation of studies published in languages other than
English.
Electronic searches
We searched the Cochrane Stroke Group Trials Register (January
2012), MEDLINE (1950 to December 2011) (Appendix 1), EM-
BASE (1980 to December 2011) (Appendix 2) and the Cochrane
Central Register of Controlled Trials (CENTRAL) (The CochraneLibrary, 2011 issue 4) (Appendix 3). We also searched the follow-ingfour Chinese databases: Chinese BiologicalMedicine Database
(CBM-disc) (1978 to December 2011), China National Knowl-
edge Infrastructure (CNKI) (1980 to December 2011), Chinese
scientific periodical database of VIP information (1989 to Decem-
ber 2011) and Wanfang Data (http://www.wanfangdata.com/)
(1982 to December 2011).The Cochrane Stroke Group Trials SearchCo-ordinatordeveloped
the search strategies for MEDLINE, EMBASE and CENTRAL
andwe adapted theMEDLINE strategy forthe Chinese databases.
Searching other resources
In an effort to identify further published, ongoing and unpub-
lished trials we contacted trialists and researchers in the field.
Data collection and analysis
Two authors (JZ, JY) read the titles, abstracts and keywords of all
records identified from the searches of the electronic bibliographic
databases and excluded studies that were clearly irrelevant. We
obtained the full text of the remaining studies and the same two
authors selected trials for inclusion based on our defined criteria
and extracted the relevant data. The two review authors resolved
any disagreements by discussion andconsulteda third author (ML)
if necessary.
Selection of studies
To identify studies for further evaluation, we scanned the titles,
abstracts and keywords of every record found. We eliminated ar-
ticles on initial screening if we could determine from the title and
abstract that the article was not a report of an RCT or the trial did
not address the effect of calcium antagonists for acute ischemic
stroke. If there was any doubt about these criteria from the infor-
mation given in the title and abstract, we obtained the full text for
clarification. We developed an inclusion/exclusion form to assist
with the selection of trials. Two review authors (JZ, JY) indepen-
dently assessed the selection of studies and they resolved any dis-
agreements through consultation with a third review author (ML).
If they could not resolve disagreements in this way, they added the
article to those awaiting assessment and we contacted the study
authors for clarification.
Data extraction and managementTwo review authors (JZ, JY) independently extracted data on
methods, patients, interventions, outcomes and results, and
recorded the information on a data extraction form. The key in-
formation extracted was as follows.
1. General information: published/unpublished, title, authors,
reference/source, contact address, country, language of
publication, year of publication, duplicate publications, sponsor,
setting.
2. Trial characteristics: design, duration of follow-up, method
of randomization, allocation concealment, blinding (patients,
people administering treatment, people assessing outcome).
3. Interventions: intervention (dose, route, frequency,
duration, time interval from the stroke onset), controlledintervention (dose, route, frequency, duration), comedication(s)
(dose, route, frequency, duration).
4. Patients: inclusion/exclusion criteria, diagnostic criteria,
total number and number in each groups, age, baseline
characteristics, similarity of groups at baseline (including any
comorbidity), assessment of compliance, withdrawals (reasons/
description), subgroups.
5. Outcomes: outcomes specified above, any other outcomes
assessed, other events, length of follow-up, quality of reporting of
outcomes.
The same two review authors cross-checked all extracted data and
resolved any disagreements by discussion. If they could not reach
consensus, the third review author (ML) made the final decision.When patients were excluded or lost to follow-up after random-
ization or if any of the above data were unavailable from the pub-
lications, we sought further information by contacting the study
authors. If such information remained unavailable, all the review
authors decided whether or not to include the trial in the review.
Assessment of risk of bias in included studies
Two review authors (JZ, JY) independently evaluatedthe following
methodological qualities of allincluded studies. They resolved any
disagreements by discussion. If they could not reach consensus,
they asked another review author (ML) to make the final decision.
Sequence generation
Was the allocation sequence adequately generated? We classified
allocation sequence as low risk, high risk or unclear risk ac-
cording to theCochrane Handbook for Systematic Reviews of Inter-ventions(Higgins 2011).
4Calcium antagonists for acute ischemic stroke (Review)
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http://www.mrw.interscience.wiley.com/cochrane/clabout/articles/STROKE/frame.htmlhttp://www.mrw.interscience.wiley.com/cochrane/clabout/articles/STROKE/frame.htmlhttp://www.wanfangdata.com/http://www.wanfangdata.com/http://www.wanfangdata.com/http://www.wanfangdata.com/http://www.mrw.interscience.wiley.com/cochrane/clabout/articles/STROKE/frame.htmlhttp://www.mrw.interscience.wiley.com/cochrane/clabout/articles/STROKE/frame.htmlhttp://www.mrw.interscience.wiley.com/cochrane/clabout/articles/STROKE/frame.html -
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Allocation concealment
Was allocation adequately concealed? We classified allocation con-
cealment as low risk, high risk or unclear risk according to the
Cochrane Handbook for SystematicReviews of Interventions(Higgins2011).
Blinding of participants, personnel and outcome assessors
Was knowledge of the allocated interventions adequately pre-
vented during the study? We classified blinding as low risk, high
risk or unclear risk according to the Cochrane Handbook for Sys-tematic Reviews of Interventions(Higgins 2011).
Incomplete outcome data
Were incomplete outcome data adequately addressed? We clas-
sified studies as low risk, high risk or unclear risk according
to theCochrane Handbook for Systematic Reviews of Interventions(Higgins 2011). If there were patients excluded or lost to follow-
up after randomization or if any of the follow-up data were not
available from the publication, we sought further information by
contacting the study authors.
Selective outcome reporting
Were reports of the study free of suggestion of selective outcome
reporting? We classified studies as low risk, high risk or unclear
risk according to theCochrane Handbook for Systematic Reviews ofInterventions(Higgins 2011).
Measures of treatment effect
These measures are listed underTypes of outcome measures.
Unit of analysis issues
None.
Dealing with missing data
SeeData extraction and management.
Assessment of heterogeneity
We tested heterogeneity among trial results using the I2 statistic.
We considered a value greater than 50% as substantial heterogene-
ity.
Assessment of reporting biases
We examined publication and other biases using a funnel plot.
We plotted effect size against sample size, resulting in a graphical
display that gave some indication of whether or not some studies
had not been published or located.
Data synthesis
We performed statistical analysis using RevMan 5.1 (RevMan
2011). We reported the results as risk ratio (RR) with 95% confi-
dence interval (CI) for dichotomous data and as mean difference
(MD) with 95% CI for continuous data. We used a random-ef-
fects model to combine individual results regardless whether there
was significant heterogeneity or not.
Subgroup analysis and investigation of heterogeneity
For the subgroup analyses we collected information about route of
drug administration, dose and time interval of start of treatment.Heterogeneity might arise from a wide variety of factors, such
as the design of the trials, the type of patients included and so
on. We also examined the influence of exclusion of the trials on
heterogeneity.
Sensitivity analysis
According to the Cochrane Handbook for Systematic Reviews of In-terventions(Higgins 2011), we re-analyzed the data of these multi-center studies. We also re-analyzed the data according to the pub-
lication status.
R E S U L T S
Description of studies
See: Characteristicsof included studies; Characteristicsof excluded
studies.
Our method of independent data collection by two authors in-
creased accuracy. Much of our data were based on original data
sets. The majorityof trialswere performedwith nimodipine. Bayer
Germany provided results of various trials. The original data sets
were often more complete than the published data. For example,
in three trials a significant number of patients were excluded af-
ter randomization and outcomes were not presented in the pub-
lication (Martinez-Vila 1990;NEST 1993;Wimalaratna 1994),
while data on these patients were available from the original data
set.
However, in the trial ofHeiss 1990, the number of excluded pa-
tients in the published article was not accounted for in the original
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data set. We did the calculations based on the original data set.
Thus, there might be a slight difference from those data in the
published article.
In this update, we added four new included studies (Nag
1998;Shibuya 2005;Squire 1996;Sze 1998). One other study
(Tanahashi 2007) was unpublished and we could not access anydata, hence we included it in the review as an ongoing study.
Results of the search
From a total of 8003 articles generated by the electronic searches
and handsearches, we identified 53 studies using calcium antag-
onists in patients with acute ischemic stroke and included 34 in
this review. The total number of included patients was 7944: we
subsequently excluded 213 patients from VENUS 1999, which
were included in the previous version of this review, as they had
hemorrhagic stroke.
Included studiesSee Characteristics of included studies. Thirty-four trials (in-
cluding 7731 patients) met the inclusion criteria (ASCLEPIOS
1990;Bogousslavsky 1990;Bridgers 1991;Canwin 1993;Capon
1983;Chandra 1995;FIST 1990;Gelmers 1984;Gelmers 1988;
German-Austrian 1994; Heiss 1990; INWEST 1990; Kaste 1994;
Kornhuber 1993; Lamsudin 1995; Limburg 1990; Lisk 1993;
Lowe 1989;Martinez-Vila 1990;Mohr 1992;Nag 1998;NEST
1993; NIMPAS 1999; Oczkowski 1989; Paci 1989; Sherman
1986; Shibuya 2005; Squire 1996; Sze 1998; TRUST 1990;
Uzunur 1995; VENUS 1999; Wimalaratna 1994; Yordanov
1984).
The age of patients in the included studies ranged from 18 to 85
years, with the average age ranging from 52.3 to 74.6 years. Mostof the trials included more males than females, which is consistent
with the fact that stroke is more common among men worldwide.
In the 34 included trials, nimodipine was used as the treatment in
26 trials, flunarizine in three trials (FIST 1990;Kornhuber 1993;
Limburg 1990), and isradipine (ASCLEPIOS 1990), nicardip-
ine (Lisk 1993), PY108-608 (Oczkowski 1989), fasudil (Shibuya
2005), and lifarizine (Squire 1996) in one trial respectively. These
calcium antagonists were administered intravenously or orally in
different dosage and different time intervals from stroke onset,
therefore we did subgroup analyses according to these different
dosages and time intervals from stroke onset.
Most trials reported that antiplatelet and anticoagulate therapy
were added to both treatment and control groups.
Death was reported in 31 trials, but only six of which reported
details of the causes of death (Capon 1983;Gelmers 1988;Kaste
1994; Kornhuber1993; Martinez-Vila1990; Sze1998). Themain
causes of death in these six trials were stroke recurrence, cardiac
infarction, cardiac failure and pneumonia.
Only 13 trials reported adverse events.There were 251/2810
(8.93%) in the treatment group and 157/2285 (6.87%) in the
control group. We defined severe adverse events as epilepsy, brady-
cardia, gastrointestinal bleeding and deep venous thrombosis.
Epilepsy occurred in three patients (3/2810, 0.11%) in the treat-
ment group and in two patients (2/2285, 0.09%) in the control
group, bradycardia occurred in two patients (2/2810, 0.07%) in
the treatment group and in two patients (2/2285, 0.09%) in thecontrol group, gastrointestinal bleeding occurred in two patients
(2/2810, 0.07%) in the treatment group and in two patients (2/
2285, 0.09%) in the control group, and deep venous thrombosis
occurred in four patients (4/2810, 0.14%) in the treatment group
and in one patient (1/2285, 0.04%) in the control group. The pa-
tients who suffered from severe hypotension (reported in six trials
with 1667 participants) were 15/827 (1.81%) in the treatment
group and 10/840 (1.2%) in the control group, and were too se-
vere to be excluded.
Excluded studies
We excluded 13 studies. For details see Characteristics of excludedstudies.
Risk of bias in included studies
Allocation
Five trials(Heiss 1990; Limburg 1990; Lowe 1989; Shibuya 2005;
Wimalaratna 1994) allocated participants by random table, one
trial (Bogousslavsky 1990) by random list, and one trial (Gelmers
1988) used a different method. Five trials (Gelmers 1988;Heiss1990; Mohr1992; Sze1998; VENUS1999) used numberedboxes
as the allocation concealment method. The remaining trials did
not report the method of random sequence generation and alloca-
tion concealment, hence we graded random sequence generation
and allocation concealment for these trials as unclear risk.
Blinding
All the trials used placebo as the control except three: one com-
pared the different results between intravenous and oral nimodip-
ine without a placebo group (Chandra 1995), and two were open
control (Gelmers 1984;Uzunur 1995).
Five trials(Canwin 1993; Capon1983; Lowe 1989; Uzunur 1995;
Yordanov 1984) did not report the method of blinding. Three
trials(Gelmers1984; Martinez-Vila1990; Sze1998) reported they
were single blind trials - two did not describe which participants
were blinded (Gelmers 1984;Martinez-Vila 1990), one reported
that the assessors were blinded (Sze1998). The remaining 26 trials
reported they were double-blind trials, but only one reported that
the assessors were blinded (Shibuya 2005).
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Incomplete outcome data
Only seven trials (Gelmers 1984;Lisk 1993;Lowe 1989;Mohr
1992;Oczkowski 1989;Shibuya 2005;VENUS 1999) reported
no patient losses at follow-up. One trial (INWEST 1990) reported
there were some patients lost but there was no difference after
an intention-to-treat (ITT) analysis of the results. We could notobtain any information about incomplete outcome data in six
trials (Capon 1983;Chandra 1995;Lowe 1989;Sherman 1986;
Uzunur 1995;Yordanov 1984); we categorized the remaining 20
trials as high risk for incomplete data since they all had data loss
and no ITT analysis.
Selective reporting
None of the trial protocols were available but it was clear from
the published reports that none included the primary outcome for
this review of death or dependency at the endof long-term follow-
up. Therefore, there was insufficient information for us to make
a judgement on selective reporting.
Other potential sources of bias
None
Effects of interventions
Primary outcome
Death or dependency at end of follow-up
Data from 22 trials with 6684 participants were available. No
difference was found between patients using calcium antagonists
or not. If anything, there may be a small but detrimental effect
(RR 1.05, 95% CI 0.98 to 1.13). For these 22 trials, there were
three drugs involved, nimodipine in 19 trials, flunarizine in two
trials and isradipine in one trial. The indirect comparisons of the
different drugs did not show clear evidence of differences between
different drugs (Analysis 1.1).
Heterogeneity was present (P = 0.09, I2 = 64%, df = 1) in the
analysis of Flunarizine versus control, in which only two trials
(FIST 1990;Limburg 1990) were included. InFIST 1990, therewere 331 participants involved while in Limburg 1990, only 26
participants were involved, the lattermight be themost substantial
cause of the heterogeneity.
A funnel plot showed obvious publication bias existed (Figure 1).
Figure 1. Funnel plot of comparison: primary outcome at end of follow-up.
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Secondary outcomes
Death at end of treatment period
Data were available from 22 trials with 6323 participants. No dif-ference was found for death at the end of treatment period (RR
1.06, 95% CI 0.93 to 1.20). In patients treated with intravenous
flunarizine we also found there was no statistically significant in-
crease in mortality, although it was related to a worse outcome
(RR 1.31, 95% CI 0.94 to 1.82) (Analysis 1.2).
A funnel plot showed there was obvious publication bias (Figure
2).
Figure 2. Funnel plot of comparison: death at end of treatment period.
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Death at end of follow-up
Data were available from 31 trials with 7483 participants. In this
analysis there was no difference found for death (RR 1.07, 95%
CI 0.98 to 1.17). In patients treated with intravenous flunarizine,
there was a statistically significant increase in mortality, which was
relatedto a worse outcome (RR 1.34, 95% CI1.01 to 1.77). Asfor
the other calcium antagonists, nimodipine, isradipine, lifarizine,
PY106-608 and nicardipine, no difference was found (Analysis
1.3).
A funnel plot showed there was obvious publication bias (Figure
3).
Figure 3. Funnel plot of comparison: death at end of follow-up.
Recurrence of stroke at end of follow-up
Only a limited number of reports mentioned stroke recurrences
(nine trials with 2460 participants). There wasno difference in the
number of events between treatment groups and control groups,
(RR0.93,95% CI 0.56 to1.54). However, the confidenceintervals
were wide (Analysis 1.4).
All adverse events during treatment period
Adverse events were more frequent in the intervention groups
(8.9% versus 6.9%). About half of the excess of adverse events in
the treatment groups were caused by thrombophlebitis due to in-
travenous administration of flunarizine (after correction for differ-
ences in the size of the active and control groups). The occurrence
of hypotension (defined as episodes leading to cessation of drug
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treatment) wasmentioned in only fivetrials andwas more frequent
in the treatment group (1.8% versus 1.2%). Very limited data on
mean systolic blood pressure in three trials supported this. The
difference was statistically significant, but very small. Bias might
play a role here, as studies would be more likely to present blood
pressure data if imbalances occurred.In the largest flunarizine trial there was a clear increase of adverse
events in the treated group (33% versus 10%, RR 3.16, 95% CI
1.91 to 5.21). This was mainly due to an excess of superficial
thrombophlebitis inthe flunarizine group.In therest of thestudies
there was no difference in adverse events. The overall result was a
RR of 1.18 (95% CI 0.81 to 1.74) (Analysis 1.5).
Heterogeneity was strongly present in this analysis, caused by the
results of the intravenous flunarizine trialFIST 1990, the consid-
erable heterogeneity could be completely reversed by removing it.A funnel plot showed there was obvious publication bias (Figure
4).
Figure 4. Funnel plot of comparison: adverse events (all) during treatment period.
Hypotension during treatment period
In six trials with 1667 participants episodes of hypotension (suf-ficient to stop treatment) were mentioned. Hypotensive episodes
were more frequent in the treatment groups (1.8% versus 1.2%,
RR 1.43, 95% CI 0.61 to 3.38), but there was no statistically sig-
nificant difference (Analysis 1.6).
Mean systolic blood pressure during or at end of treatment
Data were available in three trials with 630participants. The mean
bloodpressure inthe treated groupswas onaverage 2 mmHg lower.
This was a very small difference. The result was not statisticallysignificant (MD: -1.30, 95% CI -3.92 to 1.32) (Analysis 1.7).
There was considerable heterogeneity, which could be completely
reversed by removingMartinez-Vila 1990.
Subgroup analyses
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Primary outcome by route of administration
Data were available for 23 trials: 14 trials with 5131 participants
by oral administration, eight trials with 1544 participants by intra-
venous administration, and one trial with 143 participants com-
pared oral and intravenous administration directly. Intravenous
administration was associated with a worse outcome in treatedgroups compared with placebo controls (RR 1.11, 95% CI 1.01
to 1.22). In the orally treated groups no difference was present
(RR 1.03, 95% CI 0.93 to 1.14) (Analysis 2.1).
The only direct comparison between oral and intravenous admin-
istration of nimodipine did not support the notion that intra-
venous administration was associated with poorer outcome (RR
7.10, 95% CI 0.37 to 134.96) (Chandra 1995) (Analysis 2.1).
Primary outcome by dose: indirect comparisons
Data were available for 18 trials: one trial with 529 participants
using 60 mg oral nimodipine per day, 14 trials with 4526 par-ticipants using 120 mg oral nimodipine per day, two trials with
637 participants using 240 mg oral nimodipine per day, four trials
with 552 participants using 2 mg/hour intravenous nimodipine
per day, and two trials with 329 participants using 1 mg/hour in-
travenous nimodipine per day. The indirect comparisons did not
show a clear dose-dependent treatment effect. Nimodipine, given
orally at 60 mg, 120 mg and 240 mg versus control yielded the
following risk ratios: 1.08, 0.99 and 1.07 (i.e. did not show sta-
tistically significant difference). Intravenous nimodipine of 2 mg/
hour showed a non-significant increase in the odds of the primary
outcome (RR 1.34, 95% CI 0.93 to 1.93), the significant differ-
ence in the group treated intravenously with 1 mg/hour was not
clear (RR 1.09, 95% CI 0.91 to 1.29) (Analysis 2.2).Heterogeneity existed in the analysis of nimodipine 2 mg/hour
versus control in the primary outcome by dose, and it was largely
caused byBridgers 1991. Removing this trial decreased the het-
erogeneity but did not eliminate it.
Primary outcome by dose: direct comparisons
These direct comparisons were possible in very few trials: data
were available in six trials, including one trial with 533 partic-
ipants comparing 60 mg and 120 mg oral nimodipine per day,
one trial with 532 participants comparing 60 mg and 240 mg oral
nimodipine per day, two trials with 681 participants comparing
120 mg and 240 mg oral nimodipine per day, two trials with 333
participants comparing 1 mg/hour and 2 mg/hour intravenous
nimodipine. This direct comparison showed that 120 mg was as-
sociated with slightly better results than 60 mg and 240 mg. A
dose-dependent relationship seemed to exist for intravenous ni-
modipine. For both routes, the highest doses were associated with
poorer outcome (Analysis 2.3).
Primary outcome by time start of treatment
Data were available for 32 trials, including 18 trials with 1879
participants whose treatment started within 12 hours after stroke
onset and 14 trials with 4071 participants whose treatment started
after 12 hours from stroke onset. This comparison showed early
treatment ( 12 hours after stroke onset) with calcium antago-nists was associated with an increase in the odds of primary out-
come, compared with placebo (RR 1.08, 95% CI 0.96 to 1.21).
Treatment after 12 hours gave no effect whatever (RR 1.01, 95%
CI 0.90 to 1.13). This analysis might be confounded by route of
administration (Analysis 2.4).
Sensitivity analyses
Primary outcome in multicenter placebo-controlled trials
Of the 34 included trials, 10 trials including 4012 participants
reported that their data were from multicenter placebo-controlledtrials. We did the primary outcome analysis on these 10 trials (RR
1.04, 95%CI 0.95 to 1.14) and found there wasno clear difference
between it (Analysis 3.1) and the Primary outcome at the end of
follow-up (Analysis 1.1).
Analysis 3.6: Publication status
Data were from 22 trials, including 18 trials with 5887 partici-
pants from which we could extract the primary outcome from the
published papers, and four trials with 788 participants with un-
published data. The published trials did not show an overall effect
of active treatment (RR 1.03, 95% CI 0.94 to 1.12) on primary
outcome. On the contrary, the unpublished trials were associatedwith a deleterious effect of calcium antagonist treatment, the over-
all RR was 1.14 (95% CI 1.00 to 1.30) (Analysis 3.2).
D I S C U S S I O N
This systematic review of all available data failed to demonstrate a
reduction in mortality and dependency after treatment with cal-
cium antagonists in patients with acute ischemic stroke. Due to
the large amount of data (34 trials including 7731 patients), con-
fidence intervals were narrow and the overall result was therefore
subject to limited statistical uncertainty.
Intravenous administration of calcium antagonists was not asso-
ciated with a statistically significant increased risk of primary out-
come. For nimodipine, data were available to analyze dose depen-
dency, which appeared to be present. A higher dosage (2 mg/hour)
led to a significant increase in the risk of primary outcome com-
pared with a dosage of 1 mg/hour, which was also associated with
a significant increased risk of primary outcome as compared with
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placebo. When comparing different oral dosages of nimodipine,
60 mg and 240 mg were associated with a non-significant increase
in primary outcome; 120 mg did not show any clear effect.
The quality of the included trials of calcium antagonists for is-
chemic stroke wasgenerally good. Alltrials included were placebo-
controlled trials except Chandra 1995, Gelmers 1984and Uzunur1995, and all trials used a blinding method except fivetrials. How-
ever, there were still two main drawbacks: (1) only seven trials
reported the methods of random sequence generation and only
five trials reported the method of allocation concealment, which
might lead to selection bias, and (2) we categorized incomplete
outcome as low risk in only eight trials, and as most participants
were excluded in the treatment period and lost at follow-up, this
might lead to reporting bias.
Wedid two sensitivity analyses: one based on the primary outcome
in multicenterplacebo-controlled trials and the otheron published
trials, while drawing the same conclusions.
The findings were intriguing regarding the time interval between
stroke onset and the start of treatment. Based on the previous
meta-analysis byMohr 1994, we expected to find an improved
outcome inthe early-treated group (defined as those treated within
12 hours after stroke onset). However, this was not the case. On
the contrary, early treatment was associated with a non-significant
increase in the risk of primary outcome or death. When patients
were treated late (more than 12 hours after stroke onset), no effect
of nimodipine was seen on either the primary outcome or death
alone. Our results do not confirm the positive effect reported in
the meta-analysis byMohr 1994. For the primary outcome and
mortality alone we found no effect of nimodipine. Because more
studies have become available, our study contains data from alarger number of patients. Direct comparison of the results of the
two meta-analyses was hampered by the absence of exact patient
numbers in the various outcome categories in the paper ofMohr
1994.
There has been some debate about antithrombotic properties of
some calcium antagonists (Heininger 1996; Legault 1996). We
found no influence of calcium antagonists on stroke recurrence
or myocardial infarction. However, the number of trials reporting
these data adequately was small. This might be a result of inade-
quate monitoring and reporting.
A strong argument in favor of the presence of publication bias
was found in our sensitivity analysis concerning the relationshipof publication status and treatment effect. While the published
trials showed no effect on primary outcome, unpublished trials
without exception were associated with a statistically significantly
worse outcome in the treatment group. It was quite conceivable
that more trials had remained unpublished, with perhaps similarly
negative results.
A U T H O R S C O N C L U S I O N SImplications for practice
From our review it became clear that no evidence is available to
justify the routine use of calcium antagonists in patients with acute
ischemic stroke.
Implications for research
There is no need to perform any further studies to justify the effect
of calcium antagonists in patients with ischemic stroke.
A C K N O W L E D G E M E N T S
We are grateful to the following individuals who provided trial in-
formation: Prof G Lowe, Glasgow, UK; Beverly Bowyer, Toronto,
Canada; Tina Haller, Bayer, Canada; Dr B Infeld from Melbourne,
Australia; Prof JP Mohr, New York, USA; Prof JM Orgogozo,
Bordeaux, France; Dr H Palomaki from Helsinki, Finland; Dr J
Smakman from Janssen Pharmaceutica BV, Tilburg, Netherlands;
and Dr G Uzuner, from Eskisehir, Turkey. We also thank Prof K
Heininger and Dr J Kuebler of Bayer AG, Wuppertal, Germany
who provided tabulated data of trials of nimodipine in acute is-
chemic stroke.
We thank Hazel Fraser, Managing Editor of the Cochrane StrokeGroup for lists of relevant trials from the Cochrane Stroke Group
Trials Register and Brenda Thomas, Cochrane Stroke Group Trials
Search Co-ordinator, for developing the search strategies. Dr Carl
Counsell, Prof Peter Sandercock, Dr Berge and Ashma Krishan
have also been of tremendous help.
The protocol and earlier version of the review were written by Dr
Horn and Dr Limburg. We express our gratitude to them.
We also thank Dr Chiara Menichetti (Italy) for translation and
data extraction, Dr Fangbin Zhang for help with data extraction
anddata selection andMiss Yan Li also forhelp of full text writing.
If anyone is aware of anytrials that we have omitted, pleasecontact
Professor Ming Liu.
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R E F E R E N C E S
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ASCLEPIOS 1990 {unpublished data only}
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ischemic cerebral infarction. An overview of theASCLEPIOS programme.Drugs1990;40 Suppl 2:527.
Bogousslavsky 1990 {published and unpublished data}
Bogousslavsky J, Regli F, Zumstein V, Kobberling W.
Double-blind study of nimodipine in non-severe stroke.
European Neurology1990;30:236.
Bridgers 1991 {published and unpublished data}
Bridgers SL, Koch G, Munera C, Karwon M, Kurtz NM.
Intravenous nimodipine in acute stroke: interim analysis of
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Canwin 1993 {published and unpublished data}
Norris JW, LeBrun LH, Anderson BA, The Canwin Study
Group. Intravenous nimodipine in acute ischaemic stroke.
Cerebrovascular Diseases1994;4:1946.Capon 1983 {unpublished data only}
Nimodipine for acute ischaemic stroke (unpublished study).
Bayer AG, Wuppertal, Germany.
Chandra 1995 {published data only}
Chandra B. A new form of management of stroke. Journal
of Stroke and Cerebrovascular Diseases1995;5:2413.
FIST 1990 {published and unpublished data}
Franke CL, Palm R, Dalby M, Hantson L, Eriksson B,
Lang-Jenssen L, et al.Flunarizine in stroke treatment (FIST).
A double-blind, placebo-controlled trial in Scandinavia and
the Netherlands. Acta Neurologic Scandinavica1996;93:
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Gelmers 1984 {published and unpublished data}Gelmers HJ. The effects of nimodipine on the clinical course
of patients with acute ischemic stroke. Acta Neurologica
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Gelmers 1988 {published and unpublished data}
Gelmers HJ, Gorter K, De Weerdt CJ, Wiezer HJA. A
controlled trial of nimodipine in acute ischemic stroke.New
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German-Austrian 1994 {published and unpublished data}
Kramer G, Tettenborn B, Schmutzhard E, Aichner
F, Schwartz A. Nimodipine in acute ischemic stroke.
Results of the nimodipine German-Austrian stroke trial.
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Heiss 1990 {published and unpublished data}
Heiss WD, Holthoff V, Pawlik G, Neveling M. Effect of
nimodipine on regional cerebral glucose metabolism in
patients with acute ischemic stroke as measured by positron
emission tomography. Journal of Cerebral Blood Flow and
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INWEST 1990 {published and unpublished data}
Wahlgren NG, MacMahon DG, De Keyser J, Ryman T,
INWEST Study Group. Intravenous nimodipine West
European Stroke Trial (INWEST) of nimodipine in the
treatment of acute ischaemic stroke. Cerebrovascular Diseases1994;4:20410.
Kaste 1994 {published and unpublished data}
Kaste M, Fogelholm R, Erila T, Palomaki H, Murros K,Rissanen A, et al.A randomized, double-blind, placebo-
controlled trial of nimodipine in acute ischemic hemishperic
stroke.Stroke1994;25:134853.
Kornhuber 1993 {published data only}
Kornhuber HH, Hartung J, Herrlinger JD, Hertel G,
Hulser P-J, Prange H, et al.Flunarizine in ischemic stroke: a
randomised, multicentre, placebo-controlled, double blind
study. Neurology Psychiatry and Brain Research 1993;1:
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Lamsudin 1995 {published data only}
Lamsudin HR. A randomized, double-blind, placebo
controlled multicenter trial with nimodipine in acute
ischaemic stroke. Unpublished.
Limburg 1990 {published and unpublished data}
Limburg M, Hijdra A. Flunarizine in acute ischemic stroke:
a pilot study. European Neurology1990;30:1212.
Lisk 1993 {published data only}
Lisk D, Grotta J, Lamki L, Tran H, Taylor J, Molony D,
et al.Should hypertension be treated after acute stroke? A
randomized controlled trial using single photon emission
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Lowe 1989 {unpublished data only}
Lowe G. Nimodipine in acute cerebral hemispheric
infarction. Unpublished (University of Glasgow).
Martinez-Vila 1990 {published and unpublished data}Martinez-Vila E, Guillen F, Villanueva JA, Matias-Guiu J,
Bigorra J, Gil P, et al.Placebo-controlled trial of nimodipine
in the treatment of acute ischemic cerebral infarction. Stroke
1990;21:10238.
Mohr 1992 {published and unpublished data}
American Nimodipine Study Group. Clinical trial of
nimodipine in acute ischemic stroke. Stroke1992;23:38.
Nag 1998 {published data only}
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NEST 1993 {published and unpublished data}Hennerici M, Kramer G, North PM, Schmitz H,
Tettenborn D, Nimodipine European Stroke Trial Group
(NEST). Nimodipine in the treatment of acute MCA
ischemic stroke. Cerebrovascular Diseases1994;4:18993.
NIMPAS 1999 {published and unpublished data}
Infeld B, Davis SM, Donnan GA, Yasaka M, Lichenstein
M, Mitchell PJ, et al.Nimodipine and perfusion changes
after stroke. Stroke1999;30:141723.
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Oczkowski 1989 {published data only}
Oczkowski WJ, Hachinski VC, Bogousslavsky J, Barnett
HJ, Carruthers SG. A double-blind, randomized trial of PY
108-068 in acute ischemic cerebral infarction. Stroke1989;
20:6048.
Paci 1989 {published data only}
Paci A, Ottaviano P, Trenta A, Iannone G, De Santis L,Lancia G, et al.Nimodipine in acute ischemic stroke:
a double-blind controlled study. Acta Neurologica
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Sherman 1986 {published data only}
Sherman DG, Easton JD, Hart RG, Sherman CP.
Nimodipine in acute cerebral infarction. A double-blind
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Shibuya 2005 {published data only}
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Squire 1996 {published data only}
Squire IB, Lees KR, Pryse-Phillip W, Kertesz A, Bamford
J, Lifarizine Study Group. The effects of lifarizine in acute
cerebral infarction: a pilot safety study. Cardiovascular
Diseases1996;6:15660.
Sze 1998 {published data only}
Sze KH, Sim TC, Wong E, Cheng S, Woo J. Effect of
nimodipine on memory after cerebral infarction. Acta
Neurologica Scandinavica1998;97:38692.
TRUST 1990 {published and unpublished data}
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Uzunur 1995 {published and unpublished data}
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between nimodipine and systemic blood pressure and pulse
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Bayer AG, Wuppertal, Germany.
References to studies excluded from this review
Ameriso 1992 {published data only}
Ameriso SF, Wenby RB, Meiselman HJ, Fisher M.
Nimodipine and the evolution of hemorheological
variables after acute ischemic stroke. Journal of Stroke and
Cerebrovascular Diseases1992;2:225.
Csiba{published data only (unpublished sought but not used)}
Csiba L. Hungarian Nimodipine Trial. Unpublished.
Dalal 1995 {published data only}
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in acute ischemic cerebrovascular disease. Journal of the
Association of Physicians of India1995;43(6):3947.
Fagan 1988 {published data only}
Fagan SC, Gengo FM, Bates V, Levine SR, Kinkel WR.
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stroke in humans. Stroke1988;19:4012.
Marn Gmez 1988 {published data only}
Marn Gmez N, Soto Mas JA, Aguilar Martnez JL,
Bermdez Garca JM, Salim A, Ramos Jimnez A, et al.A
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Matias-Guiu J, Molto JM, Galiano L, Insa R, Falip R,
Martin R. Pilot double-blind placebo controlled trial of
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Molto 1994 {published data only}
Molto JM, Falip R, Martin R, Insa R, Pastor I, Matias
Guiu J. Comparative study of nicardipine versus placebo
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nicardipina frente a placebo en la prevencion del deterioro
cognitivo en los pacientes con accidentes isquemicos
transitorios].Revista de Neurologia1995;23:548.
Orgogozo {published data only (unpublished sought but not used)}
Nicardipine Stroke Trial. Unpublished work.
Petrogiannopoulos 96 {published data only}
Petrogiannopoulos G, Zaharof A, Tzoumani A, Poulikakos
J. Efficacy of long term treatment with nimodipine on brain
function after acute ischemic stroke. European Journal of
Neurology1996;3 Suppl 5:35.
Rosenbaum 1990 {published data only}
Rosenbaum DM, Zabramski JM, Fry J, Yatsu F, Marler J,Spetzler RF, et al.Early treatment of ischemic stroke with a
calcium antagonist. Stroke1991;22:43741.
Rosselli 1992 {published data only}
Rosselli A, Landini G, Castagnoli A, Vannucchi L,
Mugnaini C, Calacoci S, et al.The nimodipine therapy of
acute focal cerebral ischemia (minor stroke). A clinical
study with an assessment of regional cerebral blood flow by
SPECT.Recenti Progressi in Medicina1992;83(2):858.
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Szczechowski 1994 {published data only}
Szczechowski L, Wajgt A. Ocena skutecznosci Ieczenia
ostrych udarow niedokrwiennych dozylnym wlewem
nimodypiny. Neurologia i Neurochirurgia Polska1994;28:
299306.
Yao 1991 {published data only}
Yao J. Preliminary study of nimodipine in acute cerebralinfarction. Chinese Journal of Nervous & Mental Diseases
1991;17(1):47.
References to studies awaiting assessment
Davalos 1989 {published data only}
Davalos A, Cendra E, Gonzalez B, Genis D, Teruel J, Ruibal
A. Double-blind randomized clinical trial of nicardipine
versus placebo in acute ischemic stroke: clinical, radiological
and biochemical evaluation of the ischemic area. Preliminay
results.Neurology India1989;37 Suppl:283.
Davalos Errando 1992 {published data only}
Davalos Errando E, De Cendra E, Geris D, Teruel J, Ruibal
A, Musoles S. Double blind controlled trial of nicardipineversus placebo in the treatment of the acute phase of
cerebral infarction [Ensayo clinico controlado a doble ciego
de nicardipino frente a placebo en el tratamiento de la fase
aguda del infarto cerebral]. Neurologia1992;7:157.
Garcia Tigeria{published data only}
Garcia Tigera J, Alvarez LG, Hernandez MO. Treatment
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Hakim 1989 {published data only}
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Marchal G, et al.The effect of nimodipine on the evolution
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References to ongoing studies
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Unpublished.
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Interobserver agreement for the assessment of handicap in
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Counsell 1994
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Di Mascio 1994
Di Mascio R, Marchioli R, Tognomi G. From
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Gelmers 1990
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Mees 2008
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Nimodipine improves cerebral blood flow and neurologic
recovery after complete cerebral ischemia in the dog. Journal
of Cerebral Blood Flow and Metabolism1983;3:3843. Indicates the major publication for the study
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C H A R A C T E R I S T I C S O F S T U D I E S
Characteristics of included studies [ordered by study ID]
ASCLEPIOS 1990
Methods Publication status: unpublished
Multicenter placebo-controlled trial
Random sequence generation: unclear
Concealment: unclear
Double-blind
Exclusions during trial: unclear
Losses to follow-up: 4
Participants Inclusion criteria: age: 45 to 85 years, start within 12 hours, probable MCA infarction,
CT scan within 72 hours
Exclusion: massive hemispherical infarction, Orgogozo score > 65, clinical resolutionwithin 24 hours
Interventions Treatment: intravenous isradipine, 28 days, 80 microgram/hour for 72 hours, followed
orally with 2.5 mg bid
Placebo: identical regimen
Outcomes Barthel Index
Deaths
Last follow-up: 3 months
Dependency measurement used in review: Barthel Index
Missing: 4 patients in isradipine group
Notes Data available from principal investigator (JM Orgogozo)
Risk of bias
Bias Authors judgement Support for judgement
Random sequence generation (selection
bias)
Unclear risk Not mentioned
Allocation concealment (selection bias) Unclear risk Not mentioned
Incomplete outcome data (attrition bias)
All outcomes
High risk Missing 4 patients in isradipine group with-
out ITT analysis
Blinding of participants and personnel
(performance bias)
All outcomes
Low risk Double-blind
Blinding of outcome assessment (detection
bias)
All outcomes
Low risk Double-blind
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Bogousslavsky 1990
Methods Publication status: published
Unicenter placebo-controlled trialRandom sequence generation: random list
Concealment: unclear
Double-blind
Exclusions during trial: 8
Losses to follow-up: 1
Participants Inclusion criteria: age 40 to 85 years, start within 48 hours, acute ischemic stroke of
mild-to-moderate severity (Mathew Scale score 50 to 75), diagnosis on CT scan and
clinical evaluation
Exclusion criteria: rapid improvement < 24 hours, loss of consciousness, brainstem in-
farction, pregnancy, cerebral neoplasm, other causeof brain infarction than atherothrom-
bosis, other severe diseases, medication (concomitant use of calcium channel antagonists,
piracetam, pentoxyphylline, naftidrofuryl dehydrogenoxalate, dihydroergetoxine, alpha-methyldopa)
Interventions Treatment: oral nimodipine, 30 mg qid for 2 weeks
Placebo: identical regimen
Outcomes Mathew Scale score
Death
Last follow-up: 4 months
Dependency measurement used in review: functional item Mathew Scale scale
Missing: 1 patient in placebo group
Notes Data available from publication and database of Bayer AG, Wuppertal, Germany
Risk of bias
Bias Authors judgement Support for judgement
Random sequence generation (selection
bias)
Low risk The patients received nimodipine or
placebo according to a random list
Allocation concealment (selection bias) Unclear risk Not mentioned
Incomplete outcome data (attrition bias)
All outcomes
High risk 60 patients recruited but only 52 patients
had been analyzed, there was no ITT anal-
ysis
Blinding of participants and personnel
(performance bias)
All outcomes
Low risk Double-blind
Blinding of outcome assessment (detection
bias)
Low risk Double-blind
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Bogousslavsky 1990 (Continued)
All outcomes
Bridgers 1991
Methods Publication status: published as abstract
Multicenter placebo-controlled trial
Random sequence generation: unclear
Concealment: unclear
Double-blind
Exclusions during trial: unclear
Losses to follow-up: 1
Participants Inclusion criteria: acute stroke, moderate to severe, < 24 hours after stroke onset
Exclusion criteria: unknown
Interventions Treatment: intravenous nimodipine, 2 active groups: 1 mg/hour or 2 mg/hour for 5days, followed by oral nimodipine 120 mg/day days 5 to 21
Placebo: identical regimen
Outcomes Barthel Index, Glasgow Outcome Scale and Mathew Scale
Deaths
Last follow-up: 21 days (?not completely clear)
Dependency measurement used in review: Glasgow Outcome Scale
Missing: 1 missing in placebo group
Notes Data available from published abstract and Bayer AG, Wuppertal
Trial was stopped after inclusion of 204 of planned 720 patients because of deleterious
effect in high dosage group
Risk of bias
Bias Authors judgement Support for judgement
Random sequence generation (selection
bias)
Unclear risk Not mentioned
Allocation concealment (selection bias) Unclear risk Not mentioned
Incomplete outcome data (attrition bias)
All outcomes
High risk 1 missing in the placebo group and there
was no ITT analysis
Blinding of participants and personnel
(performance bias)
All outcomes
Low risk Double-blind
Blinding of outcome assessment (detection
bias)
All outcomes
Low risk Double-blind
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Canwin 1993
Methods Publication status: published
Placebo-controlled trial
Random sequence generation: unclear
Concealment: unclearBlinding: unclear
Exclusions during trial: 25
Losses to follow-up: 16
Participants Inclusion criteria: age 45 to 85 years, start within 48 hours, hemiplegia, CT-confirmed
hemispheric cerebral infarction, Toronto Stroke Scale scores > 20
Exclusion: coma, no motor weakness, brainstem strokes or previous strokes, CT scan
not compatible with ischemic stroke, use of calcium antagonists, concurrent terminal
illness
Interventions Treatment: intravenous nimodipine; days 1 to 10 at 2 mg/hour, days 11 to 6 months at
180 mg/day orally
Placebo: identical regimen
Outcomes Toronto Stroke Scale
Functional disability using 3 categories:(1) minoror no disability, (2) moderate disability,
(3) severely disabled or bedridden
Death
Last follow-up: 1 year
Dependency measurement used in review: Toronto Stroke Scale
Missing: 5 in active treatment group, 11 in control group
Notes Data available from publication, principal investigator, Bayer Canada and Bayer AG,
Wuppertal, Germany
Risk of bias
Bias Authors judgement Support for judgement
Random sequence generation (selection
bias)
Unclear risk Not mentioned
Allocation concealment (selection bias) Unclear risk Not mentioned
Incomplete outcome data (attrition bias)
All outcomes
High risk 189 patients randomized into the study but
164 were suitable for statistical evaluation,
and they did do the ITT analysis
Blinding of participants and personnel
(performance bias)
All outcomes
Unclear risk Not mentioned
Blinding of outcome assessment (detection
bias)
All outcomes
Unclear risk Not mentioned
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Capon 1983
Methods Publication status: unpublished
Placebo-controlled trial
Random sequence generation: unclear
Concealment: unclearBlinding: unclear
Exclusions during trial: unclear
Losses to follow-up: unclear
Participants Stroke patients, criteria unknown
Interventions Treatment: nimodipine oral, 30 mg qid for 56 days
Placebo: identical regimen
Outcomes Death
Last follow-up: at end of treatment
No dependency measurement available
Notes Very limited data available from Bayer AG, Wuppertal, Germany. No published data
Chandra 1995
Methods Publication status: published
Blinded comparison of oral versus intravenous administration of nimodipine
Random sequence generation: unclear
Concealment: unclear
Double-blind
Exclusions during trial: unclear
Losses to follow-up: 0
Placebo-controlled
Participants Inclusion criteria: sudden focal neurologic deficit, admission within 6 hours
Exclusion: transientsigns, large (> 60 mLon CT) cerebral hemorrhage; no informed con-
sent; recent myocardial infarction; congestive heart failure; abnormal renal, pulmonary
or hepatic function
Interventions Treatment: oral versus intravenous treatment: arm 1: oral nimodipine 30 mg qid and
intravenous placebo; arm 2: nimodipine 2.5 mg/hour intravenous and oral placebo
Treatment period 10 days, followed by oral nimodipine for all
Outcomes Unmodified Mathew Scale, Barthel Index
DeathLast follow-up: day 14
Dependency: data reported in unusable way
Missing: none
Notes Data from original publication, only average scores on functional items available, hence
not used in meta-analysis
This trial is only used for direct comparison of route of administration
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Chandra 1995 (Continued)
Risk of bias
Bias Authors judgement Support for judgement
Random sequence generation (selection
bias)
Unclear risk Not mentioned
Allocation concealment (selection bias) Unclear risk Not mentioned
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk Not mentioned
Blinding of participants and personnel
(performance bias)
All outcomes
Low risk Double-blind
Blinding of outcome assessment (detection
bias)
All outcomes
Low risk Double-blind
FIST 1990
Methods Publication status: published
Multicenter placebo-controlled trial
Random sequence generation: unclear
Concealment: unclear
Double-blind
Exclusions during trial: 32Losses to follow-up: 5
Participants Inclusion criteria: clinical diagnosis of ischemic stroke in MCA territory, disabling motor
deficit, total Glasgow Coma Score > 3, < 24 hours of stroke onset
Exclusion criteria: brain tumor, intracranial hemorrhage or lacunar infarction on CT
scan, previous disabling stroke, other severe disorder, poor physical or mental condition
Interventions Treatment: intravenous flunarizine: days 1 to 7 at 25 mg bid fol lowedbyoral flunarizine:
days 8 to 14 at 21 mg/day; days 15 to 28 at 7 mg/day
Placebo: identical regimen
Outcomes Modified Rankin scale, Orgogozo scale, Modified Barthel Index
DeathLast follow-up: 24 weeks
Dependency measurement used in review: Modified Rankin scale
Missing: 4 in active treatment, 1 in placebo group
Notes Other stroke therapies were not allowed
Data were available from publication and from Janssen Pharmaceutica BV, Tilburg,
Netherlands
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FIST 1990 (Continued)
Risk of bias
Bias Authors judgement Support for judgement
Random sequence generation (selection
bias)
Unclear risk Not mentioned
Allocation concealment (selection bias) Unclear risk Not mentioned
Incomplete outcome data (attrition bias)
All outcomes
High risk 331 patients recruited, but only 290 ana-
lyzed, ITT analysis performed but results
not reported
Blinding of participants and personnel
(performance bias)
All outcomes
Low risk Double-blind
Blinding of outcome assessment (detection
bias)
All outcomes
Low risk Double-blind
Gelmers 1984
Methods Publication status: published
Placebo-controlled trial
Random sequence generation: unclear
Concealment: unclear
Single-blindExclusions during trial: 0
Losses to follow-up: 0
Participants Inclusion criteria: acute ischemic stroke, age > 40 years, CT scan compatible with diag-
nosis
Exclusion criteria: not described
Interventions Treatment: oral nimodipine, 30 mg qid, 28 days
Placebo: none
Outcomes Mathew Stroke Scale
Death
Last follow-up: 28 daysDependency measurement used in review: functional item in Mathew Scale
Missing: none
Notes All patients standard treatment with 10% depolymerized dextran for 12 hours/day for
5 days
Data available from publication and Bayer AG, Wuppertal, Germany
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Gelmers 1984 (Continued)
Risk of bias
Bias Authors judgement Support for judgement
Random sequence generation (selection
bias)
Unclear risk Not mentioned
Allocation concealment (selection bias) Unclear risk Not mentioned
Incomplete outcome data (attrition bias)
All outcomes
Low risk 60 patients recruited and no data loss
Selective reporting (reporting bias) Unclear risk Not mentioned
Blinding of participants and personnel
(performance bias)
All outcomes
Low risk Single-blind
Blinding of outcome assessment (detection
bias)
All outcomes
High risk
Gelmers 1988
Methods Publication status: published
Multicenter placebo-controlled trial
Random sequence generation: computer-generated lists
Concealment: numbered boxDouble-blind
Exclusions during trial: 22
Losses to follow-up: 38
Participants Inclusion criteria: age > 45 years, clinical diagnosis of complete acute ischemic stroke 45 years,acute completed ischemic stroke; admission < 48 hours,
Mathew Scale Score < 66
Exclusion criteria: other causes than atherothrombosis, overt sys